The present invention relates to emulsions comprising highly fluorinated or perfluorinated compounds. More particularly, it relates to fluorocarbon emulsions having superior particle size stability during storage.
Fluorocarbon emulsions find uses as therapeutic and diagnostic agents. Most therapeutic uses of fluorocarbons are related to the remarkable oxygen-carrying capacity of these compounds. One commercial biomedical fluorocarbon emulsion, Fluosol (Green Cross Corp., Osaka, Japan), is presently used as a gas carrier to oxygenate the myocardium during percutaneous transluminal coronary angioplasty (R. Naito, K. Yokoyama, Technical Information Series No. 5 and 7, 1981). Fluorocarbon emulsions have also been used in diagnostic applications such as imaging. Radiopaque fluorocarbons such as perflubron (perfluorooctyl bromide or C.sub.8 F.sub.17 Br) are particularly useful for this purpose.
It is important that fluorocarbon emulsions intended for medical use exhibit particle size stability. Emulsions lacking substantial particle size stability are not suitable for long term storage, or they require storage in the frozen state. Emulsions with a short shelf life are undesirable. Storage of frozen emulsions is inconvenient. Further, frozen emulsions must be carefully thawed, reconstituted by admixing several preparations, then warmed prior to use, which is also inconvenient.
Davis et al., U.S. Pat. No. 4,859,363, disclose stabilization of perfluorodecalin emulsion compositions by mixing a minor amount of a higher boiling perfluorocarbon with the perfluorodecalin. Preferred higher boiling fluorocarbons were perfluorinated saturated polycyclic compounds, such as perfluoroperhydrofluoranthene. Others have also utilized minor amounts of higher boiling fluorocarbons to stabilize emulsions. See, e.g., Meinert, U.S. Pat. No. 5,120,731 (fluorinated morpholine and piperidine derivatives), and Kabalnov, et al., Kolloidn Zh. 48: 27-32 (1986) (F-N-methylcyclohexylpiperidine).
Davis, et al. suggested that the primary phenomenon responsible for instability of small particle size fluorocarbon emulsions was Ostwald ripening. During Ostwald ripening, an emulsion coarsens through migration of molecules of the discontinuous phase from smaller to larger droplets. See generally, Kabalnov, et al., Adv. Colloid Interface Sci. 38: 62-97 (1992). The force driving Ostwald ripening appears to be related to differences in vapor pressures that exist between separate droplets. Such a difference in vapor pressure arises because smaller droplets have higher vapor pressures than do larger droplets. However, Ostwald ripening may only proceed where the perfluorocarbon molecules are capable of migrating through the continuous phase between droplets of the discontinuous phase. The Lifshits-Slezov equation relates Ostwald ripening directly to water solubility of the discontinuous phase. See Lifshits, et al., Soy. Phys. JETP 35: 331 (1959).
It is known that addition of higher molecular weight compounds, having lower vapor pressures and lower solubility in the continuous phase, reduces such interparticle migration. This, in turn, reduces Ostwald ripening and improves particle size stability. Thus, the conventional prior art solution to the particle size stability problem is to add a certain amount (e.g., 10-30% of the fluorocarbon content) of a higher molecular weight fluorocarbon to the discontinuous phase.
Fluorocarbon emulsion particles are taken up and temporarily retained by cells of the reticuloendothelial system (RES). It is desirable to minimize this retention time. Unfortunately, when the prior art included higher molecular weight fluorocarbons in fluorocarbon emulsions, organ retention times were also increased considerably. Organ retention time for most fluorocarbons bears an exponential relationship to the molecular weight of the fluorocarbon. See J. G. Riess, Artificial Organs 8: 44, 49-51; J. G. Riess, International Symposium on Blood Substitutes, Bari, Italy: Jun. 19-20, 1987, Proceedings pp. 135-166.
There is a need for perfluorocarbon emulsions that exhibit both storage stability in the nonfrozen state and a rapid rate of elimination from the body. Accordingly, it is an object of the invention to provide fluorocarbon emulsions having these characteristics.